Summary The gastrointestinal tract is lined by a series of highly diverse epithelia that share important requirements (barrier function, innate immune function, secretory and absorptive functions), but also have distinct and highly specialized functions. Long-term maintenance of intestinal homeostasis depends on processes that maintain this morphological and functional diversity and reestablish it during regenerative episodes. Age-related loss of functional diversity can lead to metaplastic diseases, such as Barrett?s esophagus, that are associated with intestinal dysplasias and cancers. How aging affects compartment maintenance in the gut, and whether improving maintenance of compartment identities increases lifespan remains unclear. Here, the applicant presents preliminary data suggesting that age-related gastric metaplasia is caused by chronic inflammation and that it contributes to the loss of homeostasis of the aging gastrointestinal tract. Using Drosophila as a model system, the applicant finds that the JAK/Stat signaling pathway is chronically activated in differentiated cells of the aging gastric epithelium, and that this activation results in trans- differentiation of these cells into cell types characteristic of the posterior midgut epithelium. This metaplasia results in pH imbalance, commensal dysbiosis, and epithelial dysplasia, and shortens the lifespan of the animal. Accordingly, limiting JAK/Stat activity in the gastric region is sufficient to extend lifespan. Understanding the complex relationship of systemic inflammation, gastric metaplasia, and intestinal degeneration is expected to integrate various aspects of the pathophysiology of aging, providing new potential avenues for intervention. The applicant proposes the following specific aims: (i) establish the role of systemic and local inflammatory signals in the observed gastric metaplasia, (ii) characterize the mechanism of trans-differentiation of gastric cells into posterior midgut cells, (iii) assess the physiological consequences (including homeostasis of the intestinal epithelium and the commensal bacterial population, as well as lifespan) of compartment disruption in aging animals. Since the signaling mechanisms controlling regeneration in the gastrointestinal tract and the signals mediating systemic inflammatory responses are conserved between flies and vertebrates, it can be anticipated that the proposed study will provide important insight into the relationship between systemic inflammation and regenerative homeostasis in humans, and point to potential intervention strategies to improve homeostasis in the elderly and extend life- and healthspan.